Sustained delivery of an active agent using an implantable system

ABSTRACT

The invention is directed to a device for delivering an active agent formulation for a predetermined administration period. An impermeable reservoir is divided into a water-swellable agent chamber and an active agent formulation chamber. Fluid from the environment is imbibed through a semipermeable plug into the water-swellable agent chamber and the active agent formulation is released through a back-diffusion regulating outlet. Delivery periods of up to 2 years are achieved.

CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application is a continuation-in-part application of aprovisional application (serial number as yet unknown) which was filedon Feb. 2, 1996 as regular U.S. application Ser. No. 08/595,761 andconverted to a provisional application via a petition filed on Jan. 21,1997.

TECHNICAL FIELD

[0002] This invention is related to the sustained delivery of abiologically active agent. More particularly, the invention is directedto an implantable delivery system for the prolonged delivery of anactive agent to a fluid environment in a natural or artificial bodycavity.

BACKGROUND OF THE INVENTION

[0003] Treatment of disease by prolonged delivery of an active agent ata controlled rate has been a goal in the drug delivery field. Variousapproaches have been taken toward delivering the active agents.

[0004] One approach involves the use of implantable diffusional systems.For example, subdermal implants for contraception are described byPhilip D. Darney in Current Opinion in Obstetrics and Gynecology 1991,3:470-476. Norplant® requires the placement of 6 levonorgestrel-filledsilastic capsules under the skin. Protection from conception for up to 5years is achieved. The implants operate by simple diffusion, that is,the active agent diffuses through the polymeric material at a rate thatis controlled by the characteristics of the active agent formulation andthe polymeric material. Darney further describes biodegradable implants,namely Capranor™ and norethindrone pellets. These systems are designedto deliver contraceptives for about one year and then dissolve. TheCapranor™ systems consist of poly(ε-caprolactone) capsules that arefilled with levonorgestrel and the pellets are 10% pure cholesterol with90% norethindrone.

[0005] Implantable infusion pumps have also been described fordelivering drugs by intravenous, intra-arterial, intrathecal,intraperitoneal, intraspinal and epidural pathways. The pumps areusually surgically inserted into a subcutaneous pocket of tissue in thelower abdomen. Systems for pain management, chemotherapy and insulindelivery are described in the BBI Newsletter, Vol. 17, No. 12, pages209-211, December 1994. These systems provide for more accuratelycontrolled delivery than simple diffusional systems.

[0006] One particularly promising approach involves osmotically drivendevices such as those described in U.S. Pat. Nos. 3,987,790, 4,865,845,5,057,318, 5,059,423, 5,112,614, 5,137,727, 5,234,692 and 5,234,693which are incorporated by reference herein. These devices can beimplanted into an animal to release the active agent in a controlledmanner for a predetermined administration period. In general, thesedevices operate by imbibing fluid from the outside environment andreleasing corresponding amounts of the active agent.

[0007] The above-described devices have been useful for deliveringactive agents to a fluid environment of use. Although these devices havefound application for human and veterinary purposes, there remains aneed for devices that are capable of delivering active agents,particularly potent unstable agents, reliably to a human being at acontrolled rate over a prolonged period of time.

SUMMARY OF THE INVENTION

[0008] Implantable osmotic systems for delivery of an active agent to ananimal are well known. Adaptation of these systems for human use raisesa number of difficult issues. The size of the device may need to bedecreased for human implantation. The strength of the device must besufficient to ensure a robust system. Accurate and reproducible deliveryrates and durations must be ensured and the period from implantation tostart-up of delivery must be minimized. The active agent must return itspurity and activity for extended periods of time at the elevatedtemperatures encountered in the body cavity.

[0009] Accordingly, in one aspect, the invention is a fluid-imbibingdevice for delivering an active agent formulation to a fluid environmentof use. The device comprises a water-swellable, semipermeable materialthat is received in sealing relationship with the interior surface atone end of an impermeable reservoir. The device further contains anactive agent to be displaced from the device when the water-swellablematerial swells.

[0010] In another aspect, the invention is directed to an implantabledevice for delivering an active agent to a fluid environment of use. Thedevice comprises a reservoir and a back diffusion regulating outlet in amating relationship. The flow path of the active agent comprises apathway formed between the mating surfaces of the back diffusionregulating outlet and the reservoir.

[0011] In yet another aspect, the present invention is directed to adevice for storing an active agent in a fluid environment of use duringa predetermined administration period, the device comprising a reservoircontaining an active agent. The reservoir is impermeable and formed atleast in part from a metallic material. The portion of the reservoircontacting the active agent is non-reactive with the active agent, andis formed of a material selected from the group consisting of titaniumand its alloys.

[0012] In a further aspect, the invention is an implantablefluid-imbibing active agent delivery system that comprises animpermeable reservoir. The reservoir contains a piston that divides thereservoir into an active agent containing chamber and a water-swellableagent containing chamber. The active agent containing chamber isprovided with a back-diffusion regulating outlet. The water-swellableagent containing chamber is provided with a semipermeable plug. Eitherthe plug or the outlet is releasable from the reservoir at an internalpressure that is lower than the maximum osmotic pressure generated bythe water-swellable agent.

[0013] The invention is further directed to a fluid-imbibing implantableactive agent delivery system where the time to start-up of delivery isless than 10% of the predetermined administration period.

[0014] In another aspect, the invention is directed to a method forpreparing a fluid-imbibing implantable active agent delivery system. Themethod comprises injection molding a semipermeable plug into the end ofan impermeable reservoir such that the plug is protected by thereservoir.

[0015] In still another aspect, the invention is directed to animpermeable active agent delivery system for delivering an active agentthat is susceptible to degradation. The reservoir contains a piston thatdivides the reservoir into a water-swellable agent chamber and an activeagent chamber. The open end of the water-swellable agent chambercontains a semipermeable membrane and the open end of the active agentchamber contains a back-diffusion regulating outlet. The systemeffectively seals the active agent chamber and isolates it from theenvironment of use.

[0016] In a further aspect, the invention is directed to aback-diffusion regulating outlet useful in an active agent deliverysystem. The outlet defines a flow path wherein the length, interiorcross-sectional shape and area provide for an average linear velocity ofactive agent that is higher than the linear inward flow of fluid in theenvironment of use.

[0017] The invention is also directed to a semipermeable plug useful inan active agent delivery system. The plug is water-swellable and mustexpand linearly in the delivery system to commence pumping uponinsertion of the system into the fluid environment of use.

[0018] The invention is further directed to implantable delivery systemsuseful for delivering leuprolide.

DESCRIPTION OF THE DRAWINGS

[0019] The figures are not drawn to scale, but are set forth toillustrate various embodiments of the invention. Like numbers refer tolike structures.

[0020]FIGS. 1 and 2 are partial cross-sectional views of two embodimentsof the delivery device of the invention.

[0021]FIG. 3 is an enlarged cross-sectional view of the back-diffusionregulating outlet of FIG. 1.

[0022]FIG. 4 is a graph that shows the effect of orifice diameter andlength on drug diffusion.

[0023]FIGS. 5, 6, 7 and 8 are enlarged cross-sectional views of furtherembodiments of the semipermeable plug end of the reservoir according tothe invention.

[0024]FIGS. 9, 10 and 11 are graphs of release rates for systems withleuprolide (FIG. 9) and with blue dye and with different membranes(FIGS. 10 and 11).

DETAILED DESCRIPTION OF THE INVENTION

[0025] The present invention provides a device for the delivery of anactive agent to a fluid environment of use in which the active agentmust be protected from the fluid environment until it is delivered.Prolonged and controlled delivery is achieved.

DEFINITIONS

[0026] The term “active agent” intends the active agent(s) optionally incombination with pharmaceutically acceptable carriers and, optionallyadditional ingredients such as antioxidants, stabilizing agents,permeation enhancers, etc.

[0027] By a “predetermined administration period” is intended a periodof greater than 7 days, often between about 30 days and 2 years,preferably greater than about 1 month and usually between about 1 monthand 12 months.

[0028] By the time to “start-up” of delivery is intended the time frominsertion into the fluid environment of use until the active agent isactually delivered at a rate not less than approximately 70% of theintended steady-state rate.

[0029] The term “impermeable” intends that the material is sufficientlyimpermeable to environmental fluids as well as ingredients containedwithin the dispensing device such that the migration of such materialsinto or out of the device through the impermeable device is so low as tohave substantially no adverse impact on the function of the deviceduring the delivery period.

[0030] The term “semipermeable” intends that the material is permeableto external fluids but substantially impermeable to other ingredientscontained within the dispensing device and the environment of use.

[0031] As used herein, the terms “therapeutically effective amount” or“therapeutically effective rate” refer to the amount or rate of theactive agent needed to effect the desired biologic or pharmacologiceffect.

[0032] The active agent delivery devices of the invention find use wherethe prolonged and controlled delivery of an active agent is desired. Inmany cases the active agent is susceptible to degradation if exposed tothe environment of use prior to delivery and the delivery devicesprotect the agent from such exposure.

[0033]FIG. 1 shows one embodiment of the device according to theinvention. In FIG. 1 a fluid-imbibing system 10 is shown that comprisesan impermeable reservoir 12. The reservoir 12 is divided into twochambers by a piston 16. The first chamber 18 is adapted to contain anactive agent and the second chamber 20 is adapted to contain afluid-imbibing agent. A back-diffusion regulating outlet 22 is insertedinto the open end of the first compartment 18 and a water-swellablesemipermeable plug 24 is inserted into the open end of the secondchamber 20. In FIG. 1, the back-diffusion regulating outlet 22 is shownas a male threaded member in a mating relationship with the smoothinterior surface of the reservoir 12 thereby forming therebetweenhelical flow path 34. The pitch (x), the amplitude (y), and thecross-sectional area and shape of the helical Oath 34 formed between themating surfaces of the back-diffusion regulating outlet 22 and thereservoir 12 as shown in FIG. 3 are factors that affect both theefficiency of path 34 preventing back-diffusion of external fluid intothe formulation in chamber 18 and the back pressure in the device. Thegeometry of outlet 22 prevents water diffusion into the reservoir. Ingeneral, it is desired that these characteristics be selected so thatthe length of the helical flow path 34 and the velocity of flow ofactive agent therethrough is sufficient to prevent back-diffusion ofexternal fluid through the flow path 34 without significantly increasingthe back pressure, so that, following start-up, the release rate of theactive agent is governed by the osmotic pumping rate.

[0034]FIG. 2 is a second embodiment of the device of the invention witha reservoir 12, piston 16 and plug 26. In this embodiment, the flow path36 is formed between a threaded back-diffusion regulating outlet 40 andthreads 38 formed on the interior surface of the reservoir 12. Theamplitudes of the threaded portions of the back-diffusion regulatingoutlet 40 and reservoir 12 are different so that a flow path 36 isformed between the reservoir 12 and the back-diffusion regulating outlet40.

[0035] The water-swellable semipermeable plugs 24 and 26 shown in FIGS.1 and 2 respectively are inserted into the reservoir such that thereservoir wall concentrically surrounds and protects the plug. In FIG.1, the top portion 50 of the plug 24 is exposed to the environment ofuse and may form a flanged end cap portion 56 overlaying the end ofreservoir 12. The semipermeable plug 24 is resiliently engaged with theinterior surface of the reservoir 12 and in FIG. 1 is shown to haveridges 60 that serve to frictionally engage the semipermeable plug 24with the interior of reservoir 12. In addition, the ridges 60 serve toproduce redundant circumferential seals that function before thesemipermeable plug 24 expands due to hydration. The clearance betweenridges 60 and the interior surface of the reservoir 12 preventshydration swelling from exerting stresses on the reservoir 12 that canresult in tensile failure of the reservoir 12 or compression or shearfailure of the plug 24. FIG. 2 shows a second embodiment of thesemipermeable plug 26 where the plug is injection molded into the topportion of the reservoir and where the top of the semipermeable plug 26is flush with the top 62 of the reservoir 12. In this embodiment, thediameter of the plug is substantially less than the diameter of thereservoir 12. In both embodiments the plugs 24 and 26 will swell uponexposure to the fluid in body cavity forming an even tighter seal withthe reservoir 12.

[0036] The novel configurations of the components of the above-describedembodiments provide for implantable devices that are uniquely suited forimplantation into humans and can provide delivery devices which arecapable of storing unstable formulations at body temperatures forextended periods of time, which devices have start-up times of less than10% of the administration period and can be designed to be highlyreliable and with predictable fail safe modes.

[0037] Reservoir 12 must be sufficiently strong to ensure that it willnot leak, crack, break or distort so as to expel its active agentcontents under stresses it would be subjected to during use while beingimpermeable. In particular, it should be designed to withstand themaximum osmotic pressure that could be generated by the water-swellablematerial in chamber 20. Reservoir 12 must also be chemically inert andbiocompatible, that is, it must be non-reactive with the active agentformulation as well as the body. Suitable materials generally comprise anon-reactive polymer or a biocompatible metal or alloy. The polymersinclude acrylonitrile polymers such as acrylonitrile-butadiene-styreneterpolymer, and the like; halogenated polymers such aspolytetrafluoroethylene, polychlorotrifluoroethylene, copolymertetrafluoroethylene and hexafluoropropylene; polyimide; polysulfone;polycarbonate; polyethylene; polypropylene; polyvinylchloride-acryliccopolymer; polycarbonate-acrylonitrile-butadiene-styrene; polystyrene;and the like. The water vapor transmission rate through compositionsuseful for forming the reservoir are reported in J. Pharm. Sci., Vol.29, pp. 1634-37 (1970), Ind. Eng. Chem., Vol. 45, pp. 2296-2306 (1953);Materials Engineering, Vol. 5, pp. 38-45 (1972); Ann. Book of ASTMStds., Vol. 8.02, pp. 208-211 and pp. 584-587 (1984); and Ind. and Eng.Chem., Vol. 49, pp. 1933-1936 (1957). The polymers are known in theHandbook of Common Polymers by Scott and Roff, CRC Press, ClevelandRubber Co., Cleveland, Ohio. Metallic materials useful in the inventioninclude stainless steel, titanium, platinum, tantalum, gold and theiralloys as well as gold-plated ferrous alloys, platinum-plated ferrousalloys, cobalt-chromium alloys and titanium nitride coated stainlesssteel. A reservoir made from titanium or a titanium alloy having greaterthan 60%, often greater than 85% titanium is particularly preferred forthe most size-critical applications, for high payload capability and forlong duration applications and for those applications where theformulation is sensitive to body chemistry at the implantation site orwhere the body is sensitive to the formulation. Preferred systemsmaintain at least 70% active agent after 14 months at 37° C. and have ashelf stability of at least about 9 months, or more preferably at leastabout two years, at 2-8° C. Most preferably, systems may be stored atroom temperature. In certain embodiments, and for applications otherthan the fluid-imbibing devices specifically described, where unstableformulations are in chamber 18, particularly protein and/or peptideformulations, the metallic components to which the formulation isexposed must be formed of titanium or its alloys as described above.

[0038] The devices of this invention provide a sealed chamber 18 whicheffectively isolates the formulation from the fluid environment. Thereservoir 12 is made of a rigid, impermeable and strong material. Thewater-swellable semipermeable plug 24 is of a lower durometer materialand will conform to the shape of the reservoir to produce a liquid-tightseal with the interior of reservoir 12 upon wetting. The flow path 34isolates chamber 18 from back-diffusion of environmental fluid. Piston16 isolates chamber 18 from the environmental fluids that are permittedto enter chamber 20 through semipermeable plugs 24 and 26 such that, inuse at steady-state flow, active agent is expelled through outlet 22 ata rate corresponding to the rate at which water from the environmentflows into the water-swellable material in chamber 20 throughsemipermeable plugs 24 and 26. As a result, the plug and the activeagent formulation will be protected from damage and their functionalitywill not be compromised even if the reservoir is deformed. In addition,the use of sealants and adhesives will be avoided and the attendantissues of biocompatibility and ease of manufacture resolved.

[0039] Materials from which the semipermeable plug are made are thosethat are semipermeable and that can conform to the shape of thereservoir upon wetting and adhere to the rigid surface of the reservoir.The semipermeable plug expands as it hydrates when placed in a fluidenvironment so that a seal is generated between the mating surfaces ofthe plug and the reservoir. The strength of the seals between thereservoir 12 and the outlet 22 and the reservoir 12 and the plugs 24 and26 can be designed to withstand the maximum osmotic pressure generatedby the device. In a preferred alternative, the plugs 24 and 26 may bedesigned to withstand at least 10× the osmotic agent compartment 20operating pressure. In a further alternative the plugs 24 and 26 may bereleasable from the reservoir at an internal pressure that is lower thanthe pressure needed to release the back diffusion regulating outlet. Inthis fail safe embodiment, the water-swellable agent chamber will beopened and depressurized, thus avoiding dispelling the diffusionregulating outlet and attendant release of a large quantity of theactive agent. In other cases, where a fail-safe system requires therelease of the active agent formulation rather than the water-swellableagent formulation, the semipermeable plug must be releasable at apressure that is higher than the outlet.

[0040] In either case, the semipermeable plug must be long enough tosealably engage the reservoir wall under the operating conditions, thatis, it should have an aspect ratio of between 1:10 and 10:1 length todiameter, preferably at least about 1:2 length to diameter, and oftenbetween 7:10 and 2:1. The plug must be able to imbibe between about 0.1%and 200% by weight of water. The diameter of the plug is such that itwill sealingly fit inside the reservoir prior to hydration as a resultof sealing contact at one or more circumferential zones and will expandin place upon wetting to form an even tighter seal with the reservoir.The polymeric materials from which the semipermeable plug may be madevary based on the pumping rates and device configuration requirementsand include but are not limited to plasticized cellulosic materials,enhanced polymethylmethacrylate such as hydroxyethylmethacrylate (HEMA)and elastomeric materials such as polyurethanes and polyamides,polyether-polyamide copolymers, thermoplastic copolyesters and the like.

[0041] The piston 16 isolates the water-swellable agent in chamber 20from the active agent in chamber 18 and must be capable of sealablymoving under pressure within reservoir 12. The piston 16 is preferablymade of a material that is of lower durometer than the reservoir 12 andthat will deform to fit the lumen of the reservoir to provide afluid-tight compression seal with the reservoir 12. The materials fromwhich the piston are made are preferably elastomeric materials that areimpermeable and include but are not limited to polypropylene, rubberssuch as EPDM, silicone rubber, butyl rubber, and the like, andthermoplastic elastomers such as plasticized polyvinylchloride,polyurethanes, Santoprene®, C-Flex® TPE (Consolidated PolymerTechnologies Inc.), and the like. The piston may be of a self-loading orcompression-loaded design.

[0042] The back-diffusion regulating outlet 22 forms the deliverypathway through which the active agent flows from the chamber 18 to theimplantation site where absorption of the active agent takes place. Theseal between the outlet 22 and the reservoir 12 can be designed towithstand the maximum osmotic pressure generated within the device or tofail-safe in the modes described above. In a preferred embodiment, thepressure required to release back-diffusion regulating outlet 22 is atleast 10× the pressure required to move piston 16 and/or at least 10×the pressure in chamber 18.

[0043] The exit flow path of the active agent is the pathway 34 formedbetween the mating surfaces of the back-diffusion regulating outlet 22and the reservoir 12. The pathway length, interior cross-sectional shapeand area of the outlet path 34 or 36 are chosen such that the averagelinear velocity of the exiting active agent is higher than that of thelinear inward flux of materials in the environment of use due todiffusion or osmosis, thereby attenuating or moderating back-diffusionand its deleterious effects of contaminating the interior of the pump,destabilizing, diluting, or otherwise altering the formulation. Therelease rate of active agent can be modified by modifying the outletpathway geometry, which relationship is shown below.

[0044] The convective flow of active agent out of outlet 22 is set bythe pumping rate of the system and the concentration of active agent inchamber 20 and can be represented as follows:

Q _(ca)=(Q)(C _(a))  (1)

[0045] where

[0046] Q_(ca) is the convective transport of agent A in mg/day

[0047] Q is the overall convective transport of the agent and itsdiluents in cm³/day

[0048] C_(a) is the concentration of agent A in the formulation withinchamber 20 in mg/cm³

[0049] The diffusive flow of agent A through the material in the outlet22 is a function of agent concentration, cross-sectional configurationof flow path 34 or 36, agent diffusivity and length of flow path 34 or36, and can be represented as follows:

Q_(da)=Dπr² ΔC_(a)/L  (2)

[0050] where

[0051] Q_(da) is the diffusive transport of agent A in mg/day

[0052] D is the diffusivity through the material in path 34 or 36 incm²/day

[0053] r is the effective inner radius of the flow path in cm

[0054] ΔC_(a) is the difference between the concentration of agent A inthe reservoir and in the body outside of the outlet 22 in mg/cm³

[0055] L is the length of the flow path in cm

[0056] In general, the concentration of agent in the reservoir is muchgreater than the concentration of agent in the body outside of theorifice such that the difference, ΔC_(a) can be approximated by theconcentration of agent within the reservoir, C_(a).

Q_(da)=Dπr²C_(a)/L  (3)

[0057] It is generally desirable to keep the diffusive flux of agent atless than 10% of the convective flow. This is represented as follows:

Q _(da) /Q _(ca) =Dπr ² C _(a) /QC _(a) L=Dπr ² /QL≦0.1  (4)

[0058] Equation 4 indicates that the relative diffusive flux decreaseswith increasing volumetric flow rate and path length and increases withincreasing diffusivity and channel radius and is independent of drugconcentration. Equation 4 is plotted in FIG. 4 as a function of length(L) and diameter (d) for D=2×10⁻⁶ cm²/sec and Q=0.36 μl/day.

[0059] The diffusive flux of water where the orifice opens into chamber18 can be approximated as:

Q _(wd)(res)=C _(o) Qe ^((−QL/DwA))  (5)

[0060] where

[0061] C_(o) is the concentration profile of water in mg/cm³

[0062] Q is the mass flow rate in mg/day

[0063] L is the length of the flow path in cm

[0064] D_(w) is the diffusivity of water through the material in theflow path in cm²/day

[0065] A is the cross-sectional area of the flow path in cm²

[0066] The hydrodynamic pressure drop across the orifice can becalculated as follows: $\begin{matrix}{{\Delta \quad P} = \frac{8\quad Q\quad L\quad \mu}{\pi \quad r^{\quad 4}}} & (6)\end{matrix}$

[0067] Simultaneously solving equations (4), (5) and (6) gives thevalues shown in Table 1 where:

[0068] Q=0.38 μl/day

[0069] C_(a)=0.4 mg/μl

[0070] L=5 cm

[0071] D_(a)=2.00 E-06 cm²/sec

[0072] μ=5.00 E+02 cp

[0073] C_(w0)=0 mg/μl

[0074] D_(w)=6.00 E+06 cm²/sec TABLE 1 Drug Diffusion & PumpingEffective Pump rate Diffusion Water intrusion Pressure Drop Orifice diaCross Sec QC_(a) QD_(a) Diff/Conv QD_(w) Qdw delta P (mil) area (mm2)mg/day mg/day QD_(a)/QC_(a) mg/day mg/year psi 1 0.00051 0.152 0.00010.0005 0 0 1.55800 2 0.00203 0.152 0.0003 0.0018 1.14E-79 4.16E-770.09738 3 0.00456 0.152 0.0008 0.0041 4.79E-36 1.75E-33 0.01923 40.00811 0.152 0.0011 0.0074 8.89E-21 3.25E-18 0.00609 5 0.01267 0.1520.0018 0.0115 1.04E-13 3.79E-11 0.00249 6 0.01824 0.152 0.0025 0.01667.16E-10 2.61E-07 0.00120 7 0.02483 0.152 0.0034 0.0226 1.48E-07 5.4E-05 0.00065 8 0.03243 0.152 0.0045 0.0295  4.7E-06 0.001715 0.000389 0.04105 0.152 0.0057 0.0373 5.04E-05 0.018381 0.00024 10 0.05068 0.1520.0070 0.0461 0.000275 0.100263 0.00016 11 0.06132 0.152 0.0085 0.05580.000984 0.351771 0.00011 12 0.07298 0.152 0.0101 0.0664 0.0025040.913839 0.00008 13 0.08584 0.152 0.0118 0.0779 0.005263 1.9210270.00005 14 0.09933 0.152 0.0137 0.0903 0.00949 3.463836 0.00004 150.11402 0.152 0.0158 0.1037 0.015269 5.573195 0.00003 16 0.12973 0.1520.0179 0.1180 0.022535 8.225224 0.00002 17 0.14848 0.152 0.0202 0.13320.031114 11.35656 0.00002 18 0.18419 0.152 0.0227 0.1493 0.04077214.88166 0.00001 19 0.18295 0.152 0.0253 0.1664 0.051253 18.707280.00001 20 0.20271 0.152 0.0280 0.1844 0.062309 22.7427 0.00001

[0075] The calculations indicate that an orifice diameter of betweenabout 3 and 10 mil and a length of 2 to 7 cm is optimal for a devicewith the operating conditions described. In a preferred embodiment, thepressure drop across the orifice is less than 10% of the pressurerequired to release the back-diffusion regulating outlet 22.

[0076] The back-diffusion regulating outlet 22 preferably forms ahelical pathway 34 or 36 incorporating a long flow path with a means ofmechanically attaching the outlet into the reservoir without usingadhesives or other sealants. The back-diffusion regulating outlet ismade of an inert and biocompatible material selected from but notlimited to metals including but not limited to titanium, stainlesssteel, platinum and their alloys and cobalt-chromium alloys and thelike, and polymers including but not limited to polyethylene,polypropylene, polycarbonate and polymethylmethacrylate and the like.The flow path is usually between about 0.5 and 20 cm long, preferablybetween about 1 and 10 cm long and between about 0.001 and 0.020 inchesin diameter, preferably between about 0.003 and 0.015 inches to allowfor a flow of between about 0.02 and 50 μl/day, usually 0.2 to 10 μl/dayand often 0.2 to 2.0 μl/day. Additionally, a catheter or other systemmay be attached to the end of the back-diffusion regulating outlet toprovide for delivery of the active agent formulation at a site removedfrom the implant. Such systems are known in the art and are described,for example, in U.S. Pat. Nos. 3,732,865 and 4,340,054 which areincorporated herein by reference. Further, the flow path design may beuseful in systems other than the fluid-imbibing devices specificallydescribed herein.

[0077] The inventive device configurations described above also allowfor a minimal period of delay from start-up to steady-state flow rate.This is accomplished in part as a result of the configuration of thesemipermeable plug 24 or 26. As water is imbibed by the semipermeableplug, it swells. Radial expansion is limited by the rigid reservoir 12,thus the expansion must occur linearly, thereby pushing against thewater-swellable agent in chamber 18, which in turn pushes against thepiston 16. This allows pumping to commence prior to the time that waterreaches the water-swellable agent which otherwise would be requiredbefore pumping could commence. To facilitate reliable start-up, the flowpath 34 can be precharged with the active agent in chamber 18. Further,the geometry of the outlet 22 allows for initial delivery that isinfluenced by the concentration gradient of drug along the length of theoutlet. The start-up period is less than about 25% of the predetermineddelivery period and is often less than about 10% and usually less thanabout 5% of the predetermined delivery period. In a preferred embodimentfor a one year system, at least 70% of the steady-state flow rate isachieved by day 14.

[0078] The water-swellable agent formulation in chamber 20 is preferablya tissue tolerable formulation whose high osmotic pressure and highsolubility propels the active agent over a long period of time whileremaining in saturated solution in the water admitted by thesemipermeable membrane. The water-swellable agent is preferably selectedfor tolerability by subcutaneous tissue, at least at pumping rates andhypothetically resulting concentrations to allow inadvertent dispensingfrom implanted devices left in the patient for a longer than labeledperiod. In preferred embodiments, the water-swellable agent should notdiffuse or permeate through the semipermeable plug 24 or 26 to anyappreciable amount (e.g., less than 8%) under normal operatingconditions. Osmotic agents, such as NaCl with appropriate tablettingagents (lubricants and binders) and viscosity modifying agents, such assodium carboxymethylcellulose or sodium polyacrylate are preferredwater-swellable agents. Other osmotic agents useful as thewater-swellable agent include osmopolymers and osmagents and aredescribed, for example, in U.S. Pat. No. 5,413,572 which is incorporatedby reference herein. The water-swellable agent formulation can be aslurry, a tablet, a molded or extruded material or other form known inthe art. A liquid or gel additive or filler may be added to chamber 20to exclude air from spaces around the osmotic engine. Exclusion of airfrom the devices should mean that delivery rates will be less affectedby nominal external pressure changes (e.g., ±7 p.s.i. (±5 a.t.m.)).

[0079] The devices of the invention are useful to deliver a wide varietyof active agents. These agents include but are not limited topharmacologically active peptides and proteins, genes and gene products,other gene therapy agents, and other small molecules. The polypeptidesmay include but are not limited to growth hormone, somatotropinanalogues, somatomedin-C, Gonadotropic releasing hormone, folliclestimulating hormone, luteinizing hormone, LHRH, LHRH analogues such asleuprolide, nafarelin and goserelin, LHRH agonists and antagonists,growth hormone releasing factor, calcitonin, colchicine, gonadotropinssuch as chorionic gonadotropin, oxytocin, octreotide, somatotropin plusan amino acid, vasopressin, adrenocorticotrophic hormone, epidermalgrowth factor, prolactin, somatostatin, somatotropin plus a protein,cosyntropin, lypressin, polypeptides such as thyrotropin releasinghormone, thyroid stimulation hormone, secretin, pancreozymin,enkephalin, glucagon, endocrine agents secreted internally anddistributed by way of the bloodstream, and the like. Further agents thatmay be delivered include alantitrypsin, factor VIII, factor IX and othercoagulation factors, insulin and other peptide hormones, adrenalcortical stimulating hormone, thyroid stimulating hormone and otherpituitary hormones, interferon α, β, and δ, erythropoietin, growthfactors such as GCSF, GMCSF, insulin-like growth factor 1, tissueplasminogen activator, CD4, dDAVP, interleukin-1 receptor antagonist,tumor necrosis factor, pancreatic enzymes, lactase, cytokines,interleukin-1 receptor antagonist, interleukin-2, tumor necrosis factorreceptor, tumor suppresser proteins, cytotoxic proteins, and recombinantantibodies and antibody fragments, and the like.

[0080] The above agents are useful for the treatment of a variety ofconditions including but not limited to hemophilia and other blooddisorders, growth disorders, diabetes, leukemia, hepatitis, renalfailure, HIV infection, hereditary diseases such as cerbrosidasedeficiency and adenosine deaminase deficiency, hypertension, septicshock, autoimmune diseases such as multiple sclerosis, Graves disease,systemic lupus erythematosus and rheumatoid arthritis, shock and wastingdisorders, cystic fibrosis, lactose intolerance, Crohn's diseases,inflammatory bowel disease, gastrointestinal and other cancers.

[0081] The active agents may be anhydrous or aqueous solutions,suspensions or complexes with pharmaceutically acceptable vehicles orcarriers such that a flowable formulation is produced that may be storedfor long periods on the shelf or under refrigeration, as well as storedin an implanted delivery system. The formulations may includepharmaceutically acceptable carriers and additional inert ingredients.The active agents may be in various forms, such as uncharged molecules,components of molecular complexes or pharmacologically acceptable salts.Also, simple derivatives of the agents (such as prodrugs, ethers,esters, amides, etc.) which are easily hydrolyzed by body pH, enzymes,etc., can be employed.

[0082] It is to be understood that more than one active agent may beincorporated into the active agent formulation in a device of thisinvention and that the use of the term “agent” in no way excludes theuse of two or more such agents. The dispensing devices of the inventionfind use, for example, in humans or other animals. The environment ofuse is a fluid environment and can comprise any subcutaneous position orbody cavity, such as the peritoneum or uterus, and may or may not beequivalent to the point of ultimate delivery of the active agentformulation. A single dispensing device or several dispensing devicescan be administered to a subject during a therapeutic program. Thedevices are designed to remain implanted during a predeterminedadministration period. If the devices are not removed following theadministration, they may be designed to withstand the maximum osmoticpressure of the water-swellable agent or they may be designed with abypass to release the pressure generated within the device.

[0083] The devices of the present invention are preferably renderedsterile prior to use, especially when such use is implantation. This maybe accomplished by separately sterilizing each component, e.g., by gammaradiation, steam sterilization or sterile filtration, then asepticallyassembling the final system. Alternatively, the devices may beassembled, then terminally sterilized using any appropriate method.

PREPARATION OF THE DEVICES OF THE INVENTION

[0084] Reservoir 12 is prepared preferably by machining a metal rod orby extrusion or injection molding a polymer. The top portion of thereservoir may be open as shown in FIG. 1 or may contain a cavity asshown in FIG. 2.

[0085] Where the reservoir 12 is open as shown in FIG. 1, awater-swellable semipermeable plug 24 is inserted mechanically from theoutside of the reservoir without using an adhesive before or afterinsertion of the piston and water-swellable agent formulation. Reservoir12 may be provided with grooves or threads which engage ribs or threadson plug 24.

[0086] Where the reservoir 12 contains a cavity as shown in FIG. 2, thecavity may be cylindrical in shape, as shown in FIG. 5, it may bestepped, as shown in FIG. 6, it may be helical, as shown in FIG. 7 or itmay be in a spaced configuration, as shown in FIG. 8. The semipermeableplug 26 is then injected, inserted, or otherwise assembled into thecavity so that it forms a seal with the reservoir wall.

[0087] Following insertion of the plug 26 either mechanically, bywelding or by injection, the water-swellable agent is assembled into thereservoir followed by insertion of the piston, with appropriate stepstaken to vent entrapped air. The active agent is filled into the deviceusing a syringe or a precision dispensing pump. The diffusion moderatoris inserted into the device, usually by a rotating or helical action, orby axial pressing.

[0088] The following examples are illustrative of the present invention.They are not to be construed as limiting the scope of the invention.Variations and equivalents of these examples will be apparent to thoseof skill in the art in light of the present disclosure, the drawings andclaims herein.

EXAMPLES Example 1 Preparation of a Device with an HDPE Reservoir

[0089] A system containing leuprolide acetate for the treatment ofprostate cancer was assembled from the following components:

[0090] Reservoir (HDPE) (5 mm outside diameter, 3 mm inside diameter)

[0091] Piston (Santoprene®)

[0092] Lubricant (silicone medical fluid)

[0093] Compressed osmotic engine (60% NaCl, 40% sodium carboxymethylcellulose)

[0094] Membrane plug (Hytrel polyether-ester block copolymer, injectionmolded to desired shape)

[0095] Back diffusion Regulating Outlet (polycarbonate)

[0096] Active agent (0.78 g of 60% propylene glycol and 40% leuprolideacetate)

[0097] Assembly

[0098] The piston and inner diameter of the reservoir were lightlylubricated with silicon medical fluid. The piston 16 was inserted intothe open end of chamber 20. Two osmotic engine tablets (40 mg each) werethen inserted on top of piston 16. After insertion, the osmotic enginewas flush with the end of the reservoir. The membrane plug 24 wasinserted by lining up the plug with the reservoir and pushing gentlyuntil the plug was fully engaged in the reservoir. Active agent wasloaded into a syringe which was then used to fill chamber 18 from itsopen end by injecting the material into the open tube until theformulation was ˜3 mm from the end. The filled reservoir was centrifuged(outlet end “up”) to remove any air bubbles that have been trapped inthe formulation during filling. The outlet 22 was screwed into the openend of the reservoir until completely engaged. As the outlet was screwedin, excess formulation exited out of the orifice ensuring a uniformfill.

Example 2 Insertion of the Device of Example 1

[0099] Insertion of the device of Example 1 is done under asepticconditions using a trocar similar to that used in the implantation ofNorplant® contraceptive implants to position the device under the skin.The insertion area is typically in the inside of the upper arm, 8 to 10cm above the elbow.

[0100] The area is anesthetized and an incision is made through theskin. The incision is approximately 4 mm long. The trocar is insertedinto the incision until the tip of the trocar is at a distance of 4 to 6cm from the incision. The obturator is then removed from the trocar andthe device of Example 1 inserted into the trocar. The device is thenadvanced to the open end of the trocar using the obturator. Theobturator is then held in position, thus immobilizing the device ofExample 1 while the trocar is withdrawn over both the device and theobturator. The obturator is then removed, leaving the implant behind ina well-controlled position. The edges of the incision are then securedwith a skin closure. The area is covered and kept dry for 2 to 3 days.

Example 3 Removal of the Device of Example 1

[0101] The device of Example 1 is removed as follows: The device islocated by fingertip palpation of the upper arm area. The area at oneend of the implant is then anesthetized and an approximately 4 mm,perpendicular incision is made through the skin and any fibrous capsuletissue surrounding the implant area. The end of the device opposite theincision is pushed so that the device end proximal to the incision isurged out of the incision. Any further fibrotic tissue is cut with ascalpel. Following removal, the procedure of Example 2 can be followedto insert a new device.

Example 4 Delivery Rate of the Device of Example 1

[0102] Glass test tubes were filled with 35 ml distilled water and thenplaced in a 37° C. water bath. A single device as described in Example 1was placed in each test tube and the test tubes were changedperiodically. The delivery rate profile from the system is shown in FIG.9. The system does not have any start-up time because the systemexhibits a period of initial high release followed by a lower steadystate release for a period of 200 days.

Example 5 Delivery Rate Profiles

[0103] Glass test tubes were filled with 35 ml distilled water whichwere then placed in a 37° C. water bath. After the test tubes had comeup to temperature, a single device as described in Example 1, but withmembrane materials described below and containing 1% FD&C blue dye inwater as the drug formulation, was placed in each tube. Water from thetest tube permeated through the membrane causing the system to pumpformulation (blue dye) into the surrounding water in the test tube. Atregular intervals, systems were switched to fresh test tubes. The amountof dye released was determined by measuring the concentration of bluedye in each test tube using a spectrophotometer. The pumping rate wascalculated from the total dye released, the volume of water in the tube,the initial concentration of dye and the interval over which the systemwas in the test tube. Results for two different tests are shown in FIGS.10 and 11. FIG. 10 shows 3 different systems with different plugmaterials (Hytrel® 2, 3 and 12 month systems) and FIG. 11 shows 4systems with different plug materials. These materials are: MembraneMaterial  1 month Pebax 25 (Polyamide)  2 month Pebax 22 (Polyamide)  3month Polyurethane (HP60D) 12 month Pebax 24 (Polyamide)

[0104] The systems were capable of delivering for a period of from 2 to12 months, depending on the membrane used.

Example 6 Preparation of a Delivery Device with a Titanium Reservoir

[0105] A system containing leuprolide acetate for the treatment ofprostate cancer was assembled from the following components:

[0106] Reservoir (Titanium, Ti6Al4V alloy) (4 mm outside diameter, 3 mminside diameter)

[0107] Piston (C-Flex®)

[0108] Lubricant (silicone medical fluid)

[0109] Compressed osmotic engine (76.4% NaCl, 15.5% sodium carboxymethylcellulose, 6% povidone, 0.5% Mg Stearate, 1.6% water)

[0110] PEG 400 (8 mg added to osmotic engine to fill air spaces)

[0111] Membrane plug (polyurethane polymer, injection molded to desiredshape)

[0112] Back diffusion Regulating Outlet (polyethylene)

[0113] Drug formulation (0.150 g of 60% water and 40% leuprolideacetate)

[0114] Assembly

[0115] The piston and inner diameter of the reservoir were lightlylubricated. The piston was inserted ˜0.5 cm into the reservoir at themembrane end. PEG 400 was added into the reservoir. Two osmotic enginetablets (40 mg each) were then inserted into the reservoir from themembrane end. After insertion, the osmotic engine was flush with the endof the reservoir. The membrane plug was inserted by lining up the plugwith the reservoir and pushing gently until the retaining features ofthe plug were fully engaged in the reservoir. Formulation was loadedinto a syringe which was then used to fill the reservoir from the outletend by injecting formulation into the open tube until the formulationwas ˜3 mm from the end. The filled reservoir was centrifuged (outlet end“up”) to remove any air bubbles that have been trapped in theformulation during filling. The outlet was screwed into the open end ofthe reservoir until completely engaged. As the outlet was screwed in,excess formulation exited out of the orifice ensuring a uniform fill.

Example 7 Preparation of a Leuprolide Acetate Delivery Device with aTitanium Reservoir

[0116] A system containing leuprolide acetate for the treatment ofprostate cancer was assembled from the following components:

[0117] Reservoir (Titanium Ti6Al4V alloy) (4 mm outside diameter, 3 mminside diameter, 4.5 cm length)

[0118] Piston (C-Flex® TPE elastomer, available from ConsolidatedPolymer Technologies, Inc.)

[0119] Lubricant (silicone medical fluid 360)

[0120] Compressed osmotic engine tablet (76.4% NaCl, 15.5% sodiumcarboxymethyl cellulose, 6% povidone, 0.5% Mg Stearate, 1.5% water, 50mg total)

[0121] PEG 400 (8 mg added to osmotic engine to fill air spaces)

[0122] Membrane plug (polyurethane polymer 20% water uptake, injectionmolded to desired shape 3 mm diameter×4 mm length)

[0123] Back-diffusion Regulating Outlet (polyethylene, with 6 mil×5 cmchannel)

[0124] Drug formulation (leuprolide acetate dissolved in DMSO to ameasured content of 65 mg leuprolide)

[0125] Assembly

[0126] Systems were assembled as in Example 6, using aseptic proceduresto assemble γ-irradiated subassemblies and filled aseptically withsterile filtered leuprolide DMSO formulation.

[0127] Release Rate

[0128] These systems delivered about 0.35 μl/day leuprolide formulationcontaining on average 150 μg leuprolide in the amount delivered per day.They provide delivery of leuprolide at this rate for at least one year.The systems achieved approximately 70% steady-state delivery by day 14.

Implantation and Removal

[0129] Systems will be implanted under local anesthetic and by means ofan incision and trocar as in Example 2 to patient suffering fromadvanced prostatic cancer.

[0130] After one year, systems will be removed under local anesthetic asdescribed in Example 3. New systems may be inserted at that time.

Example 8 Treatment of Prostatic Cancer

[0131] Leuprolide acetate, an LHRH agonist, acts as a potent inhibitorof gonadotropin secretion when given continuously and in therapeuticdoses. Animal and human studies indicate that following an initialstimulation, chronic administration of leuprolide acetate results insuppression of testicular steroidogenesis. This effect is reversibleupon discontinuation of drug therapy. Administration of leuprolideacetate has resulted in inhibition of the growth of certainhormone-dependent tumors (prostatic tumors in Noble and Dunning malerats and DMBA-induced mammary tumors in female rats) as well as atrophyof the reproductive organs. In humans, administration of leuprolideacetate results in an initial increase in circulating levels ofluteinizing hormone (LH) and follicle stimulating hormone (FSH), leadingto a transient increase in levels of the gonadal steroids (testosteroneand dihydrotestosterone in males). However, continuous administration ofleuprolide acetate results in decreased level of LH and FSH. In males,testosterone is reduced to castrate levels. These decreases occur withintwo to six weeks after initiation of treatment, and castrate levels oftestosterone in prostatic cancer patients have been demonstrated formultiyear periods. Leuprolide acetate is not active when given orally.

[0132] Systems will be prepared as in Example 7, then inserted asdescribed. The continuous administration of leuprolide for one yearusing these systems will reduce testosterone to castrate levels.

[0133] The above description has been given for ease of understandingonly. No unnecessary limitations should be understood therefrom, asmodifications will be obvious to those skilled in the art.

We claim:
 1. A fluid-imbibing device for delivering an active agent to a fluid environment of use, said device comprising a water-swellable semipermeable material that is received in sealing relationship with the interior surface of one end of an impermeable reservoir and an active agent to be displaced from the device when the water-swellable material swells.
 2. The device of claim 1 wherein the semipermeable material is selected from the group consisting of plasticized cellulosic materials, polyurethanes and polyamides.
 3. The device of claim 1 wherein the aspect ratio of the plug is 1:10 to 10:1 length to diameter.
 4. The device of claim 1 wherein the semipermeable material is assembled into an open end of the reservoir.
 5. The device of claim 1 wherein the semipermeable material is assembled into a cavity in said reservoir.
 6. The device of claim 5 wherein the cavity is of a shape selected from the group consisting of a cylindrical, stepped, helical threaded and spaced configuration.
 7. The device of claim 1 wherein the active agent is selected from the group consisting of a protein, a peptide or a gene therapy agent.
 8. The device of claim 7 wherein the active agent is an LHRH agonist or antagonist.
 9. The device of claim 7 wherein the active agent is leuprolide.
 10. The device of claim 7 wherein the active agent is selected from the group consisting of Factor VIII and Factor IX.
 11. The device of claim 1 wherein the active agent is delivered to a site remote from the device.
 12. An implantable device for delivering an active agent to a fluid environment of use, said device comprising a reservoir and a back-diffusion regulating outlet in mating relationship, wherein a flow path for the active agent comprises a pathway formed between the mating surfaces of the reservoir and the back-diffusion regulating outlet.
 13. The device of claim 12 where the active agent is delivered at a rate of 0.02 to 50 μl/day.
 14. The device of claim 12 wherein the active agent is selected from the group consisting of a protein, a peptide or a gene therapy agent.
 15. The device of claim 14 wherein the active agent is leuprolide.
 16. The device of claim 12 wherein the active agent is delivered to a site remote from the device.
 17. A device for storing an active agent in a fluid environment of use during a predetermined administration period, the device comprising a reservoir containing an active agent, said reservoir being formed at least in part from a metallic material, the portion of said reservoir contacting said active agent being non-reactive with the active agent, said metallic material in contact with active agent being formed of a material selected from the group consisting of titanium and its alloys.
 18. The device of claim 17 wherein the titanium alloy is at least 60% titanium.
 19. The device of claim 17 wherein the active agent is selected from the group consisting of a protein, a peptide or a gene therapy agent.
 20. The device of claim 19 wherein the active agent is delivered to a site remote from the device.
 21. An implantable fluid-imbibing active agent delivery system comprising an impermeable reservoir and containing a piston that divides the reservoir into an active agent containing chamber and a water-swellable agent containing chamber, wherein the active agent containing chamber is provided with a back-diffusion regulating outlet and the water-swellable agent containing chamber is provided with a semipermeable plug; wherein the plug is releasable from the reservoir at an internal pressure that is lower than the maximum osmotic pressure generated by the water-swellable agent.
 22. An implantable fluid-imbibing active agent delivery system comprising an impermeable reservoir and containing a piston that divides the reservoir into an active agent containing chamber and a water-swellable agent containing chamber, wherein the active agent containing chamber is provided with a back-diffusion regulating outlet and the water-swellable agent containing chamber is provided with a semipermeable plug; wherein the outlet is releasable from the reservoir at an internal pressure that is lower than the maximum osmotic pressure generated by the water-swellable agent.
 23. A fluid-imbibing implantable active agent delivery system for delivering an active agent to a fluid environment of use for a predetermined administration period, wherein the time to start-up is less than 10% of the predetermined administration period.
 24. A method for preparing a fluid-imbibing implantable active agent delivery system for delivering an active agent to a fluid environment of use for a predetermined administration period said method comprising injection molding a semipermeable plug into the end of an impermeable reservoir such that the semipermeable plug is protected by the reservoir.
 25. The method of claim 24 wherein the semipermeable plug material is a polyurethane based material.
 26. The method of claim 24 wherein the semipermeable plug material is a polyamide based material.
 27. The method of claim 24 wherein the semipermeable plug material is a cellulosic based material.
 28. An implantable active agent delivery system for delivering an active agent to a fluid environment of use, said agent being susceptible to degradation if exposed to the fluid environment of use prior to delivery, said system comprising: (a) a piston that divides the system into a first and second chamber, the first and second chambers each having an open end; (b) a water-swellable agent formulation in the first chamber; (c) an active agent formulation in the second chamber; (d) a semipermeable plug in the open end of the first chamber; and (e) a back-diffusion regulating outlet in the open end of the second chamber; wherein said system effectively seals the active agent chamber and isolates it from the environment of use.
 29. The system of claim 28 wherein the active agent is selected from the group consisting of a protein, a peptide or a gene therapy agent.
 30. The system of claim 28 wherein the active agent is leuprolide.
 31. A back-diffusion regulating outlet useful in an active agent delivery system for delivering active agent to a fluid environment of use, said outlet defining a flow path wherein the length, interior cross-sectional shape and area provide for an average linear velocity of the active agent that is higher than the linear inward flux of the fluid environment of use.
 32. The outlet of claim 31 wherein the flow path is helical in shape.
 33. A semipermeable plug useful in an active agent delivery system for delivering an active agent to a fluid environment of use, said plug being water-swellable and expanding linearly in said delivery system to commence pumping of active agent upon insertion of the delivery system in the fluid environment of use.
 34. An implantable leuprolide delivery system comprising: (a) an impermeable reservoir; (b) a piston that divides the reservoir into a first and a second chamber, the first and second chambers each having an open end; (c) a water-swellable agent formulation in the first chamber; (d) a leuprolide formulation in the second chamber; (e) a semipermeable plug in the open end of the first chamber; and (f) a back-diffusion regulating outlet in the open end of the second chamber; wherein the system effectively seals the second chamber and isolates the leuprolide formulation from the environment of use.
 35. The system of claim 34 wherein the reservoir is titanium or a titanium alloy.
 36. The system of claim 34 wherein the piston is formed of C-Flex® TPE.
 37. The system of claim 34 wherein the water-swellable agent formulation contains at least about 64 mg NaCl.
 38. The system of claim 34 wherein the water-swellable agent formulation contains NaCl, a gelling osmopolymer and granulation and processing aids.
 39. The system of claim 34 further comprising an additive in the first chamber.
 40. The system of claim 39 wherein the additive is PEG
 400. 41. The system of claim 34 wherein the leuprolide formulation is leuprolide acetate dissolved in DMSO at an assayed content of 37% leuprolide.
 42. The system of claim 34 which contains 65 mg leuprolide.
 43. The system of claim 34 wherein the semipermeable plug is formed of polyurethane material with 20% water uptake.
 44. The system of claim 34 wherein the back-diffusion regulating outlet is made of polyethylene and has a flow path helical in shape with a diameter between 0.003 and 0.020 inches and a length of 2 to 7 cm.
 45. The system of claim 34 which delivers about 0.35 μL leuprolide formulation per day.
 46. The system of claim 45 which provides continuous delivery of leuprolide formulation for about one year.
 47. The system of claim 34 which reaches at least about 70% steady-state delivery by day
 14. 48. The system of claim 34 which delivers about 150 μg leuprolide per day.
 49. A method of treating a subject suffering from prostatic cancer comprising administering at least one system of claim
 34. 50. An implantable leuprolide delivery system comprising: (a) a titanium alloy reservoir; (b) a C-Flex® TPE piston that divides the reservoirs into a first and a second chamber, the first and second chambers each having an open end; (c) a compressed NaCl-based osmotic engine and a PEG additive in the first chamber; (d) 65 mg leuprolide as a leuprolide acetate solution in DMSO in the second chamber; (e) a semipermeable polyurethane plug with 20% water uptake in the open end of the first chamber; and (f) a polyethylene back diffusion regulating outlet with a helical flow path in the open end of the second chamber; wherein the system continuously delivers about 150 μg leuprolide per day for about one year after subcutaneous implantation. 